Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.
Amino Acid Sequence
Benzamidines
/ chemistry
Binding Sites
Drug Evaluation, Preclinical
Humans
Isomerism
Kallikreins
/ antagonists & inhibitors
Models, Molecular
Molecular Structure
Mutation
Netherton Syndrome
/ drug therapy
Protein Binding
Serine Peptidase Inhibitor Kazal-Type 5
/ genetics
Serine Proteinase Inhibitors
/ chemistry
Structure-Activity Relationship
KLK1
KLK5
KLKB1
LEKTI
Netherton syndrome
SPINK5
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
23
07
2019
revised:
04
09
2019
accepted:
05
09
2019
pubmed:
16
9
2019
medline:
23
10
2020
entrez:
16
9
2019
Statut:
ppublish
Résumé
The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.
Identifiants
pubmed: 31521475
pii: S0960-894X(19)30625-0
doi: 10.1016/j.bmcl.2019.126675
pii:
doi:
Substances chimiques
Benzamidines
0
Serine Peptidase Inhibitor Kazal-Type 5
0
Serine Proteinase Inhibitors
0
KLK5 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
benzamidine
KUE3ZY3J1F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
126675Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.